Here we show that cabergoline treatment results in an increase in GDNF level and in the subsequent activation of the GDNF pathway. Furthermore, we found that cabergoline selectively decreased ethanol-drinking and -seeking behaviors in rodents, including relapse. These actions of cabergoline are likely to be mediated by the midbrain, specifically by the VTA, because microinjection of cabergoline into this brain area was highly effective in reducing operant ethanol self-administration in rats. Finally, cabergoline failed to increase GDNF levels and to reduce ethanol consumption in GDNF heterozygous knockout mice. Together, these results suggest that cabergoline decreases ethanol-drinking and -seeking behaviors and that these effects are mediated via upregulation of the GDNF pathway in the mesolimbic system.
Previous studies showed that cabergoline treatment increases GDNF
levels and secretion of GDNF in cultured astrocytes (9
), and we found that cabergoline upregulates GDNF mRNA and protein levels in the dopaminergic-like SH-SY5Y neuroblastoma cell line. Moreover, the increase in GDNF
expression was followed by the activation of the GDNF pathway, as shown by an increase in Ret and ERK1/2 phosphorylation. Importantly, the increase in GDNF
expression and ERK1/2 phosphorylation induced by cabergoline was also observed in vivo. The source of GDNF induced by cabergoline treatment is yet to be determined and could be neurons and/or astrocytes, because GDNF is expressed in both types of cells (11
). The mechanism by which cabergoline increases GDNF synthesis is also unknown. However, cabergoline is a dopaminergic receptors agonist (7
), and in vitro studies showed that blockade of the D2Rs partially inhibited the increase in GDNF levels induced by cabergoline (9
). In addition, activation of dopaminergic receptors by the nonselective agonist apomorphine or selective D3R agonists was found to stimulate GDNF synthesis in mesencephalic neuronal cultures (32
). Therefore, activation of the dopaminergic receptors might contribute to the upregulation of GDNF levels by cabergoline.
Cabergoline did not significantly alter the self-administration of sucrose, a natural reward, in rats. These data suggest that cabergoline acts on processes induced by exposure to ethanol rather than on general rewarding and/or motivational mechanisms. Similarly, we previously reported that systemic injection of Ibogaine reduced ethanol but not sucrose consumption in rats (19
), and intra-VTA infusion of GDNF did not affect sucrose self-administration (20
). This relative selectivity of cabergoline’s action is in contrast to the approved drugs for alcohol craving, acamprosate and naltrexone, which have been shown to reduce water and sucrose consumption in rodents (34
). This lack of selectivity in naltrexone’s and acamprosate’s actions suggests a general effect on motivation that could be related, for example, to the dysphoria induced by naltrexone (36
) and the problem of compliance for both medications (4
). Furthermore, we found that cabergoline also decreased lever-responding during an extinction period when ethanol was not available, suggesting that cabergoline reduces the motivation to seek ethanol. Importantly, cabergoline was effective in two procedures that model relapse (28
). Specifically, we found that cabergoline administration reduced reacquisition of ethanol self-administration after a period of extinction and the motivation to seek ethanol after a period of abstinence. Similarly, we found that Ibogaine and GDNF decreased ethanol self-administration in models of relapse (19
). Thus, cabergoline seems to have an improved selectivity for ethanol compared with the current medications available for the treatment of alcohol dependence and relapse.
Our results suggest that the VTA is a primary site of action for cabergoline. However, a high concentration of cabergoline also decreased ethanol self-administration when the drug was micro-injected in the SNc, however, diffusion of the drug from the SNc to the VTA could account for this effect. The possibility that the SNc is not a primary site of cabergoline-mediated modulation of ethanol-drinking behaviors is also supported by our recent finding showing that GDNF infused in the SNc does not alter ethanol self-administration (20
). However, we cannot exclude the possible contribution of the SNc to cabergoline’s actions, because SNc neurons project to the dorsal striatum, a structure involved in the self-administration of drugs of abuse and alcohol (38
) and is thought to also be implicated in addictive behaviors (41
Cabergoline is an agonist of the dopaminergic adrenergic and serotoninergic receptors (6
), which were shown to decrease ethanol consumption in rodents (31
). We show here that the effect of cabergoline on ethanol consumption was detected in the GDNF+/+
mice but was abolished in GDNF+/−
mice in which cabergoline was also unable to increase GDNF
expression in the midbrain. Moreover, the GDNF+/−
mice do not differ from the wild-type mice in their number of D1R-like (44
) and in number or functionality of D2R-like (present study), suggesting that the change we observed is specific for GDNF and not due to compensatory mechanisms resulting in a differential dopaminergic response between the GDNF+/+
and the GDNF+/−
mice to cabergoline. Hence, although the pharmacological action of cabergoline on other systems might contribute to the inhibitory effect of this drug on ethanol-related behaviors, the present results suggest that GDNF is a crucial component in the action of cabergoline to reduce ethanol-drinking and -seeking.
Our findings are in agreement with a growing body of evidence suggesting a modulatory role for GDNF in addiction (45
). For example, VTA dopaminergic neurons are selectively vulnerable to neuroadaptations induced by repeated long-term exposure to drugs of abuse and ethanol (46
), and administration of GDNF into the VTA blocks these biochemical adaptations to cocaine and morphine exposure (48
). In addition, we recently reported that GDNF reverses the alteration of tyrosine hydroxylase immunoreactivity induced by prolonged ethanol exposure (45
). Furthermore, GDNF+/−
mice exhibit an increased sensitivity to morphine and psychostimulants as assessed by psychomotor sensitization, place conditioning, and self-administration procedures (45
). Conversely, intra-VTA infusion of GDNF reduces cocaine place conditioning (48
), and sustained administration of GDNF into the striatum impedes the acquisition of cocaine self-administration (45
). We previously found that the upregulation of the GDNF pathway in the VTA by Ibogaine reduces rat ethanol-drinking behaviors (19
). Similarly, Niwa et al.
) reported that increasing endogenous GDNF expression in the brain blocks methamphetamine place conditioning and psychomotor sensitization. Finally, we showed that direct infusion of GDNF into the VTA results in a rapid and sustained reduction of ethanol self-administration (20
). Importantly, GDNF blocks the ability of an ethanol prime to induce reacquisition of ethanol self-administration after an extinction period (20
), suggesting that GDNF inhibits relapse to ethanol consumption. These studies and the present findings support the idea that upregulation of the GDNF pathway in the mesolimbic system by agents such as cabergoline might be a valuable strategy to combat alcoholism and other forms of addiction.
Cabergoline is approved for marketing in several countries including the U.S. for the treatment of hyperprolactinemia (50
) and has also been used as adjunctive or monotherapy for Parkinson’s disease (52
). In Parkinsonian patients, cabergoline is used at very high doses (2–6 mg/day) that were reported to increase the risk of cardiac valvulopathy (reviewed in [54
]). However, in hyperprolactinemia, in which cabergoline is used at much lower doses (.25 to 3.5 mg/week) (51
), six recent cross-sectional studies of patients treated for several years with the drug (45–79 months) found an association between moderate valvular regurgitation only at the highest cumulative doses of cabergoline (54
). We found that systemic administration of a low dose of cabergoline (.25–.5 mg/kg) (21
) was sufficient to significantly reduce ethanol-consumption and -seeking in rodents. Furthermore, a pilot study conducted on cocaine addicts reported that cabergoline significantly reduced cocaine use, as evaluated by analysis of cocaine metabolite levels in urine samples and self-report of substance use, with a weekly dose of only .5 mg (59
). Therefore, these data suggest that low doses of cabergoline that circumvent the increasing prevalence of cardiac valvulopathy might be effective in reducing drug and alcohol abuse.
In conclusion, we found that cabergoline selectively reduces ethanol-drinking and -seeking behaviors. Moreover, we identified GDNF as the mechanism that mediates cabergoline’s actions to reduce ethanol-drinking behaviors, supporting the idea that upregulation of the GDNF pathway might be a valuable strategy for the treatment of addiction. Importantly, although in-depth clinical investigations are needed, our data suggest that cabergoline might be used as a selective medication for the treatment of alcohol addiction.